Phase IIa Proof-of-Concept Evaluation of the Antiviral Efficacy, Safety, Tolerability, and Pharmacokinetics of the Next-Generation Maturation Inhibitor GSK3640254

Abstract

Background GSK3640254 (GSK’254) is a next-generation HIV-1 maturation inhibitor with pharmacokinetics (PK) supporting once-daily therapy. Methods This phase IIa double-blind (sponsor-unblinded), randomized, placebo-controlled, adaptive study evaluated antiviral effect, safety, tolerability, and PK of once-daily GSK’254 monotherapy administered with food (moderate-fat meal) in HIV-1–positive, treatment-naive adults. In part 1, participants received GSK’254 10 or 200 mg for 10 days. In part 2, participants received GSK’254 40, 80, or 140 mg for 7 days, modified from 10 days by a protocol amendment to decrease potential for resistance-associated mutations (RAMs). The primary endpoint was maximum change from baseline in HIV-1 RNA. Results Maximum changes in HIV-1 RNA of −0.4, −1.2, −1.0, −1.5, and −2.0 log10 occurred with GSK’254 10, 40, 80, 140, and 200 mg, respectively. Regardless of dosing duration, doses ≥40 mg resulted in ≥1-log10 declines in HIV-1 RNA. Plasma PK was generally dose proportional to 140 mg but non-proportional between 140 and 200 mg. Four participants in the 200-mg group developed RAMs on Day 11 in part 1, one with phenotypic resistance. No RAMs occurred in part 2. Adverse events (AEs) were reported by 22 (65%) participants; headache was the most common (n=4). Two non–drug-related serious AEs occurred. All AEs were of mild-to-moderate intensity, except for 2 grade 3 non–drug-related AEs in 1 participant. Conclusions This monotherapy study established a dose–antiviral response relationship for GSK’254. No safety or tolerability concerns were noted. These results supported dose selection for the ongoing phase IIb study (ClinicalTrials.gov: NCT04493216).

The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation

“…At a dose of 200 mg, there was no significant difference in exposure of 9 from the tablet or capsule form of the mesylate salt form, although there was a 3- to 4-fold increase in exposure when the drug was administered with a meal of moderate fat content. In a phase IIa clinical trial to assess efficacy in HIV-1-infected subjects and determine a dose suitable for phase III studies, doses of 10 and 200 mg of 9 were administered over 10 days with a subsequent adjustment in the dosing interval to 7 days for the 40, 80, and 140 mg doses, an amendment that was designed to avoid the selection and growth of resistant virus . As summarized in Figure , doses of 40 mg and above of 9 were associated with a >1 log 10 reduction in plasma HIV-1 RNA, with drug exposure dose-proportional up to a dose of 140 mg, although the small size of the study meant that this observation was not significant.…”

“…In a phase IIa clinical trial to assess efficacy in HIV-1-infected subjects and determine a dose suitable for phase III studies, doses of 10 and 200 mg of 9 were administered over 10 days with a subsequent adjustment in the dosing interval to 7 days for the 40, 80, and 140 mg doses, an amendment that was designed to avoid the selection and growth of resistant virus. 35 As summarized in Figure 4, doses of 40 mg and above of 9…”

“…While the initial phase of the SAR survey that led to the discovery of 4 had emphasized the uniqueness of the para -substituted benzoic acid moiety incorporated at C-3 of the triterpenoid core, subsequent studies identified the spiro cyclobutene moiety found in 5 and 6 and the cyclohexene that characterizes 7 and 8 as effective scaffolds on which to project the crucial pharmacophoric carboxylic acid moiety (Figure ). − ,, In this article, we describe further studies with 7 and 8 in which the effect of substituents installed α- to the carboxylic acid moiety are explored and led to the discovery of GSK3640254 ( 9 ) as an MI with an optimized antiviral profile that has been advanced into clinical study. ,− …”

Relative Bioavailability and Food Effect of GSK3640254 Tablet and Capsule Formulations in Healthy Participants

“…Pharmacokinetic analysis showed that GSK3640254 was slowly absorbed, with a median time to maximum observed concentration (t max ) of 3.0 hours and an estimated half‐life of approximately 22.6 hours for the 200‐mg dose, supportive of once‐daily dosing 5 . In the phase IIa proof‐of‐concept study in treatment‐naive adults with HIV‐1 (NCT03784079), the GSK3640254 200‐mg dose resulted in an approximately 2‐log 10 reduction in plasma HIV‐1 RNA with no noted safety or tolerability concerns 6 . GSK3640254 is an inhibitor of uridine diphosphate glucuronosyltransferase 1A1 and organic anion‐transporting polypeptide 1B3 in vitro 7,8 .…”

“…In both phase I and phase IIa proof‐of‐concept studies, GSK3640254 was formulated as a mesylate salt in a capsule 5,6 . In planned phase IIb studies, the proposed formulation for GSK3640254 is a mesylate salt in a tablet.…”